6640 J. Med. Chem. 2010, 53, 6640–6652 DOI: 10.1021/jm1005989
Inhalation by Design: Novel Ultra-Long-Acting β2-Adrenoreceptor Agonists for Inhaled Once-Daily Treatment of Asthma and Chronic Obstructive Pulmonary Disease That Utilize a Sulfonamide Agonist Headgroup ) )
Paul A. Glossop,*,† Charlotte A. L. Lane,*,† David A. Price,†,# Mark E. Bunnage,† Russell A. Lewthwaite,† Kim James,† Alan D. Brown,† Michael Yeadon,‡ Christelle Perros-Huguet,‡,§ Michael A. Trevethick,‡ Nicholas P. Clarke,‡, Robert Webster,§ Rhys M. Jones,§ Jane L. Burrows,^ Neil Feeder,^ Stefan C. J. Taylor,^ and Fiona J. Spence Department of Worldwide Medicinal Chemistry, ‡Allergy and Respiratory Research Unit, §Department of Pharmacokinetics, Dynamics, and Metabolism, Department of Drug Safety, and ^Department of Pharmaceutical Sciences, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Kent CT13 9NJ, U.K. # Present address: Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340. )
†
Received May 17, 2010
A novel series of potent and selective sulfonamide derived β2-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties was achieved through targeted introduction of a phenolic moiety to support rapid phase II clearance, thereby minimizing systemic exposure following inhalation and reducing systemically mediated adverse events. Compound 38 (PF-610355) is identified as a clinical candidate from this series, with in vivo duration of action studies confirming its potential for once-daily use in humans. Compound 38 is currently in advanced phase II clinical studies. Introduction
Chart 1
Respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPDa) are highly prevalent diseases that affect millions of people worldwide. Long acting β2-adrenoreceptor agonists are a highly precedented drug class used for the treatment of asthma and COPD. There are currently two marketed long-acting β2-adrenoreceptor agonists (LABAs), salmeterol and formoterol (Chart 1), which exhibit sufficient duration of action to support twicedaily dosing regimens following inhaled delivery. However, neither of these agents are approved for once-daily dosing. A major area of current focus in the respiratory field is to identify novel, ultra-long-acting β2-adrenoreceptor agonists that are suitable for use as once-a-day inhaled agents, either as stand-alone therapies or for use in combination products with other bronchodilator and/or anti-inflammatory agents. The improved patient convenience and compliance associated with such once-a-day treatments, especially when delivered in convenient dry powder inhaler devices, is expected to support much more effective therapy for both asthma and COPD. *To whom correspondence should be addressed. For P.A.G.: phone, þ44 1304 649188; fax, þ441304651821; e-mail, paul.glossop@pfizer. com. For C.A.L.L.: phone, þ441304648231; fax, þ441304651813; e-mail,
[email protected]. a Abbreviations: ACh, acetylcholine; cAMP, cyclic adenosine monophosphate; CHO, Chinese hamster ovary; COPD, chronic obstructive pulmonary disease; DDI, drug-drug interaction; DoA, duration of action; DPI, dry powder inhaler; DSC, differential scanning calorimetry; DVS, dynamic vapor sorption; EFS, electrical field stimulation; GPT, guinea pig trachea; LABA, long-acting β2-adrenoreceptor agonist; PXRD, powder X-ray diffraction; sGAW, specific airway conductance; TGA, thermogravimetric analysis.
pubs.acs.org/jmc
Published on Web 08/30/2010
A number of reports from our laboratories and others have described various chemical series that offer promise as inhaled once-daily β2-adrenoreceptor agonists.1-9 Indacaterol (QAB149) is the most advanced agent (Chart 2), having been recently approved as its maleate salt in the European Union (2009) and launched (2010) as the Onbrez Breezhaler for oncedaily treatment of COPD.3 Advanced agents from other efforts include milveterol (GSK-159797),4 vilanterol (GSK642444),5 and olodaterol (BI-1744-CL)6 that have largely been progressed to phase II trials in asthma and phase III trials in COPD (Chart 2). We have previously reported the design and profile of two novel series of β2-adrenoreceptor agonists exemplified by compounds 1, 2, and 3 (Chart 3).7-9 In addition, 1 and 3 have been disclosed as compounds that were selected as development candidates.10 Both compounds r 2010 American Chemical Society
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Chart 2
Chart 3. Structures of Previously Disclosed Pfizer β2-Adrenoreceptor Agonists
Chart 4
met our criteria for progression, including high levels of potency, long duration of action (DoA) in vitro and in vivo, and suitable pharmacokinetics for inhaled delivery (low oral absorption, rapid systemic clearance). However, while 3 possessed good material properties as its crystalline L-tartrate salt, compatible with delivery from a dry powder inhaler, it was generally found that securing suitable solid form characteristics in this conformationally flexible and lipophilic series presented a significant challenge. Therefore, as part of our strategy to identify additional development candidates, we sought to identify a differentiated series of β2-adrenoreceptor agonists with higher intrinsic crystallinity to simplify solid form identification and candidate selection. In this paper we describe the discovery of a novel series of β2-adrenoreceptor agonists that combine the pharmacology profile required for once-daily dosing potential with the robust solid form attributes necessary to support convenient delivery in a preferred dry-powder inhaler device. This “inhalation by design” philosophy culminated in the discovery of compound 38 as a clinical candidate that is currently in advanced phase II studies for the treatment of asthma and COPD. Chemistry The target compounds in this paper have architecture similar to that of 2 (Chart 3) while utilizing the sulfonamide headgroup found in zinterol (Chart 4). The synthetic strategy for preparation of these targets was based upon two primary disconnections that lead to the key bromo alcohol “head”, amino ester “linker”, and amine “tail” fragments (Scheme 1).
The key sulfonamide headgroup 4 was prepared according to literature methods.11 Selective N-mesylation to give 5 was followed by O-silylation to afford the protected intermediate 6 (Scheme 2). The monomethyl substituted linker 7 was prepared from 3-bromophenylacetic acid (Scheme 3). Esterification followed by palladium-mediated coupling with isoprenyl acetate gave the keto ester intermediate 8. Reductive amination with R-(R)methylbenzylamine gave the protected amino ester as a mixture of diastereomers in a 4:1 ratio (R,R-9a/R,S-9b). Selective crystallization of the desired R,R diastereomer 9a as the hydrochloride salt was followed by transfer hydrogenation to give the aminoester 7 in good yield and high enantiomeric excess (Scheme 3). The 1,1-dimethyl substituted linker 10 was prepared from 2,20 -(1,3-phenylene)diacetic acid (Scheme 4). Esterification of the diacid with ethanol gave the diester 11, which was equilibrated with further diacid under acidic conditions to give a statistical mixture of the desired monoester 12, together with diacid and diester. Treatment of the monoester 12 with excess methyl Grignard reagent in tetrahydrofuran gave the tertiary alcohol 13. Standard Ritter conditions with acetonitrile were used to convert the alcohol to the acetamide; however, subsequent cleavage of the resulting acetamide proved problematic.12 Treatment of the acetamide in refluxing sodium hydroxide in ethylene glycol resulted in decomposition, and acid hydrolysis was very slow. Further examination of the literature identified a modified Ritter procedure, using chloroacetonitrile rather than acetonitrile as the nitrogen source.13 Yields for the rearrangement reaction increased, and the resulting R-chloroacetamide 14 was readily cleaved by treatment with thiourea in refluxing acetic acid, followed by esterification to give the aminoester 10 in good yield (Scheme 4). Coupling of 6 and the linkers 7 and 10 was effected by direct displacement of the bromide in the absence of solvent to give the key ester intermediates 15 and 16 (Scheme 5). The use of solvent and triethylamine as base was investigated; however, no advantage was found over the neat reaction. Ester hydrolysis of template 15 with aqueous lithium hydroxide gave the
6642 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 18
Glossop et al.
Scheme 1. General Retrosynthetic Strategy for Preparation of Target Compounds
Scheme 2a
a
Reagents: (a) MeSO2Cl, pyridine, DCM, 16.5 h, 88%; (b) TBDMSCl, imidazole, DMAP, DMF, 16 h, 86%.
Scheme 3a
a Reagents: (a) (i) MeOH, H2SO4; (ii) Bu3SnOMe, isoprenyl acetate, P(o-tolyl)3, Pd(OAc)2, toluene, 100 C, 5 h, 94%; (b) R-(R)-methylbenzylamine, NaBH(OAc)3, AcOH, DCM, 48 h; (c) (i) HCl, MeOH; (ii) recrystallization, DIPE, MeOH, 40% (two steps); (d) 20% Pd(OH)2/C, NH4HCO2, MeOH, 75 C, 1.5 h, 100%.
Scheme 4a
Reagents: (a) EtOH, AcCl, reflux, 18 h, 92%; (b) 2,20 -(1,3-phenylene)diacetic acid, EtOH, 1,4-dioxane, HCl, reflux, 18 h, 27%; (c) MeMgCl, THF, 18 h, 100%; (d) chloroacetonitrile, H2SO4, AcOH, 4 h, 96%; (e) (i) thiourea, AcOH, EtOH, reflux, 16 h; (ii) HCl, MeOH, reflux, 16 h, 67%. a
carboxylic acid intermediate 17, whereas transfer hydrogenation of 16 afforded phenol 18. Subsequent debenzylation of 17 and ester hydrolysis of 18 afforded key acid intermediates 19 and 20, respectively. Target compounds were generally prepared by active ester couplings of acids 17, 19, and 20 with appropriate amines to provide 21a-38a, followed by full deprotection to afford test compounds 21-38. In the majority of cases, deprotection was achieved via ammonium fluoride mediated desilylation (22, 24, 26-38), although some examples required additional debenzylation prior to final desilylation (21, 23, 25) (Scheme 6). For target compounds 21-29 the amine coupling partners were commercially available; however, for phenolic compounds 30-38 some of the amines required de novo synthesis according to one of four general methods: (1) reduction of
benzonitriles with borane, (2) reductive amination of benzaldehydes with allylamine followed by Pd-mediated deprotection with dimethylbarbituric acid, (3) amide coupling of benzoic acids with ammonia followed by reduction with borane, and (4) Pd-mediated Suzuki coupling of phenolic boronic acids with Boc-protected halobenzylamines to afford bespoke biaryl systems.14 Results and Discussion Our strategy to identify a differentiated series of β2-adrenoreceptor agonists with higher intrinsic crystallinity focused on retention of the key β2-pharmacophore combined with additional chemical motifs known to predispose compounds toward greater crystallinity. Sulfonamides were of particular
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Scheme 5a
a
Reagents: (a) neat, 90 C, 16-72 h, 58-80%; (b) LiOH, THF, 48-72 h, 90-100%; (c) 20% Pd(OH)2/C, NH4HCO2, EtOH, 85 C, 3 h, 65-84%.
Scheme 6a
a Reagents: (a) R6R5NH, 1-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, iPr2NEt, DMF, 18 h, 31-85%; (b) 20% Pd(OH)2/C, NH4HCO2, EtOH, 85 C, 3 h; (c) NH4F, EtOH, H2O, 50 C, 18 h, 38-93%.
interest given their capacity for formation of hydrogen-bonding interactions and salt bridges and their presence in the headgroup of the β2-adrenoreceptor agonist zinterol (Chart 4). In addition to its potential to confer crystallinity, with the sulfonamide moiety being one of the most effective H-bond donors, it also had the potential to further reduce oral absorption across the gut wall in a manner consistent with our “inhalation by design” objectives, namely, to minimize systemic exposure and maximize therapeutic index (TI) through reduced oral bioavailability (of the swallowed fraction following inhalation) and increased hepatic clearance.8 There have been numerous analyses investigating molecular properties that influence good oral absorption/bioavailability, and a feature that most of them agree upon is the preference to minimize hydrogen bonding character.15 One example of this type of analysis is Lipinski’s so-called “rule-of-five” (Ro5), in which H-bond donors (8 10 μM). In vitro genetic toxicity testing and in vivo rat toleration studies were also completed without observing any meaningful adverse effects. The tussivity of 38 was evaluated in a clinically validated rabbit lung cough model that measures action potentials from Aδ-fibres/rapidly adapting receptors
Table 4. In Vitro and In Vivo Pharmacokinetic Data for Compound 38 in vitro PK
rat in vivo PK -6
Caco-2 Papp 10
(cm/s)
iv
compd
HLM Clint ((μL/min)/mg)
A-B
B-A
Vd (L/kg)
ClT ((mL/min)/kg)
t1/2 (h)
rat ppb (%)
po F (%)
38
54
